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      Noradrenaline Increases mEPSC Frequency in Pyramidal Cells in Layer II of Rat Barrel Cortex via Calcium Release From Presynaptic Stores

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          Abstract

          Somatosensory cortex is innervated by afferents originating from the locus coeruleus which typically release noradrenaline. We tested if activation of presynaptic α 1-adrenoceptors (AR) coupled to a G q-mediated signaling cascade resulted in calcium (Ca 2+) release from stores and thereby increased spontaneous transmitter release in rat barrel cortex. Adding 1–100 μM noradrenaline (NA) or 5 μM cirazoline (CO), a α 1-AR specific agonist, to the standard artificial cerebrospinal fluid increased the frequency of miniature excitatory postsynaptic currents (mEPSC) by 64 ± 7% in 51% of pyramidal cells in layer II (responders) with no effect on the amplitude. In 42 responders, the mEPSC frequency during control was significantly smaller (39 ± 2 vs. 53 ± 4 Hz) and upon NA exposure, the input resistance ( R in) decreased (9 ± 7%) compared to non-responders. Experiments using CO and the antagonist prazosin revealed that NA acted via binding to α 1-ARs, which was further corroborated by simultaneously blocking β- and α 2-ARs with propranolol and yohimbine, which did not prevent the increase in mEPSC frequency. To verify elements in the signaling cascade, both the phospholipase C inhibitor edelfosine and the membrane permeable IP 3 receptor blocker 2-APB averted the increase in mEPSC frequency. Likewise, emptying Ca 2+ stores with cyclopiazonic acid or the chelation of intracellular Ca 2+ with BAPTA-AM prevented the frequency increase, suggesting that the frequency increase was caused by presynaptic store release. When group I metabotropic glutamate receptors were activated with DHPG, co-application of NA occluded a further frequency increase suggesting that the two receptor activations may not signal independently of each other. The increased mEPSC frequency in a subset of pyramidal cells results in enhanced synaptic noise, which, together with the reduction in R in, will affect computation in the network.

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          A network model of catecholamine effects: gain, signal-to-noise ratio, and behavior.

          At the level of individual neurons, catecholamine release increases the responsivity of cells to excitatory and inhibitory inputs. A model of catecholamine effects in a network of neural-like elements is presented, which shows that (i) changes in the responsivity of individual elements do not affect their ability to detect a signal and ignore noise but (ii) the same changes in cell responsivity in a network of such elements do improve the signal detection performance of the network as a whole. The second result is used in a computer simulation based on principles of parallel distributed processing to account for the effect of central nervous system stimulants on the signal detection performance of human subjects.
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            Projection-specific neuromodulation of medial prefrontal cortex neurons.

            Mnemonic persistent activity in the prefrontal cortex (PFC) constitutes the neural basis of working memory. To understand how neuromodulators contribute to the generation of persistent activity, it is necessary to identify the intrinsic properties of the layer V pyramidal neurons that transfer this information to downstream networks. Here we show that the somatic dynamic and integrative properties of layer V pyramidal neurons in the rat medial PFC depend on whether they project subcortically to the pons [corticopontine (CPn)] or to the contralateral cortex [commissural (COM)]. CPn neurons display low temporal summation and accelerate in firing frequency when depolarized, whereas COM neurons have high temporal summation and display spike frequency accommodation. In response to dynamic stimuli, COM neurons act as low-pass filters, whereas CPn neurons act as bandpass filters, resonating in the theta frequency range (3-6 Hz). The disparate subthreshold properties of COM and CPn neurons can be accounted for by differences in the hyperpolarization-activated cyclic nucleotide gated cation h-current. Interestingly, neuromodulators hypothesized to enhance mnemonic persistent activity affect COM and CPn neurons distinctly. Adrenergic modulation shifts the dynamic properties of CPn but not COM neurons and increases the excitability of CPn neurons significantly more than COM neurons. In response to cholinergic modulation, CPn neurons were much more likely to display activity-dependent intrinsic persistent firing than COM neurons. Together, these data suggest that the two categories of projection neurons may subserve separate functions in PFC and may be engaged differently during working memory processes.
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              Kinetics of PIP2 metabolism and KCNQ2/3 channel regulation studied with a voltage-sensitive phosphatase in living cells

              The signaling phosphoinositide phosphatidylinositol 4,5-bisphosphate (PIP2) is synthesized in two steps from phosphatidylinositol by lipid kinases. It then interacts with KCNQ channels and with pleckstrin homology (PH) domains among many other physiological protein targets. We measured and developed a quantitative description of these metabolic and protein interaction steps by perturbing the PIP2 pool with a voltage-sensitive phosphatase (VSP). VSP can remove the 5-phosphate of PIP2 with a time constant of τ <300 ms and fully inhibits KCNQ currents in a similar time. PIP2 was then resynthesized from phosphatidylinositol 4-phosphate (PIP) quickly, τ = 11 s. In contrast, resynthesis of PIP2 after activation of phospholipase C by muscarinic receptors took ∼130 s. These kinetic experiments showed that (1) PIP2 activation of KCNQ channels obeys a cooperative square law, (2) the PIP2 residence time on channels is <10 ms and the exchange time on PH domains is similarly fast, and (3) the step synthesizing PIP2 by PIP 5-kinase is fast and limited primarily by a step(s) that replenishes the pool of plasma membrane PI(4)P. We extend the kinetic model for signaling from M1 muscarinic receptors, presented in our companion paper in this issue (Falkenburger et al. 2010. J. Gen. Physiol. doi:10.1085/jgp.200910344), with this new information on PIP2 synthesis and KCNQ interaction.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                27 July 2018
                2018
                : 12
                : 213
                Affiliations
                [1] 1Neuronal Network Laboratory, Eccles Institute of Neuroscience, The John Curtin School of Medical Research, Australian National University , Canberra, ACT, Australia
                [2] 2Division of Cerebral Circuitry, National Institute for Physiological Sciences , Okazaki, Japan
                [3] 3Zhejiang Provincial Key Laboratory of Anesthesiology, The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University , Wenzhou, China
                [4] 4ANU Medical School, Australian National University , Canberra, ACT, Australia
                Author notes

                Edited by: Christian Lohr, Universität Hamburg, Germany

                Reviewed by: Christine E. Gee, Universität Hamburg, Germany; Ruth M. Empson, University of Otago, New Zealand

                *Correspondence: Christian Stricker, christian.stricker@ 123456anu.edu.au
                Article
                10.3389/fncel.2018.00213
                6072855
                30100867
                7f5b9ef9-341f-4cc6-982a-4357550ebae7
                Copyright © 2018 Choy, Agahari, Li and Stricker.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 21 December 2017
                : 28 June 2018
                Page count
                Figures: 5, Tables: 2, Equations: 1, References: 61, Pages: 16, Words: 0
                Categories
                Neuroscience
                Original Research

                Neurosciences
                α1-adrenoceptor,presynaptic calcium stores,mepsc,noradrenaline,neuromodulation
                Neurosciences
                α1-adrenoceptor, presynaptic calcium stores, mepsc, noradrenaline, neuromodulation

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